rs267606892

Variant names:

• chrM-10563-T-C
• rs267606892
• ENST00000361335.1:c.94T>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The m.10563T>C (p.C32R) variant in MT-ND4L has not been reported in individuals with primary mitochondrial disease to our knowledge. The computational predictors APOGEE1 and APOGEE2 produce conflicting evidence regarding the predicted functional impact of this variant with raw scores of 0.42 (neutral) and 0.840 (likely pathogenic), respectively (Min=0, Max=1). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on October 23, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PM2_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA250589/MONDO:0044970/015

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-ND4L ENST00000361335.1 missense
• Scores: Apogee2 Pathogenic 0.84
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:1 No linked disesase in Mitomap
• Conservation: PhyloP100: 4.73
• Publications: 2 publications found

Genes affected

MT-ND4L (HGNC:7460): (mitochondrially encoded NADH 4L dehydrogenase) Predicted to enable NADH dehydrogenase (ubiquinone) activity. Predicted to be located in mitochondrial inner membrane. Implicated in Leber hereditary optic neuropathy and diabetes mellitus. [provided by Alliance of Genome Resources, Apr 2022]

MT-ND4 (HGNC:7459): (mitochondrially encoded NADH dehydrogenase 4) Enables NADH dehydrogenase (ubiquinone) activity. Involved in mitochondrial electron transport, NADH to ubiquinone and mitochondrial respiratory chain complex I assembly. Part of mitochondrial respiratory chain complex I. Implicated in Leber hereditary optic neuropathy; Parkinson's disease; macular degeneration; and schizophrenia. Biomarker of Alzheimer's disease. [provided by Alliance of Genome Resources, Apr 2022]

MT-ND3 (HGNC:7458): (mitochondrially encoded NADH dehydrogenase 3) Enables NADH dehydrogenase (ubiquinone) activity. Involved in mitochondrial electron transport, NADH to ubiquinone. Part of mitochondrial respiratory chain complex I. Implicated in Leber hereditary optic neuropathy; Leigh disease; and Parkinson's disease. [provided by Alliance of Genome Resources, Apr 2022]

TRNR (HGNC:7496): (mitochondrially encoded tRNA arginine)

TRNR Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000361335.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT-ND4L	ENST00000361335.1	TSL:6	c.94T>C	p.Cys32Arg	missense	Exon 1 of 1	ENSP00000354728.1
	MT-ND4	ENST00000361381.2	TSL:6	c.-197T>C		upstream_gene	N/A	ENSP00000354961.2
	MT-ND3	ENST00000361227.2	TSL:6	c.*159T>C		downstream_gene	N/A	ENSP00000355206.2

Frequencies

Mitomap GenBank The variant is not present, suggesting it is rare .

Alfa AF: 0.00 Hom.: 0

Mitomap

No disease associated.

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Familial colorectal cancer Pathogenic:1

Nov 01, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Mitochondrial disease Uncertain:1

Oct 23, 2023

ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The m.10563T>C (p.C32R) variant in MT-ND4L has not been reported in individuals with primary mitochondrial disease to our knowledge. The computational predictors APOGEE1 and APOGEE2 produce conflicting evidence regarding the predicted functional impact of this variant with raw scores of 0.42 (neutral) and 0.840 (likely pathogenic), respectively (Min=0, Max=1). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on October 23, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.84
Hmtvar	Pathogenic	0.89
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Benign	-0.13	T
DEOGEN2	Benign	0.20	T
LIST_S2	Benign	0.81	T
PhyloP100		4.7
PROVEAN	Pathogenic	-12	D
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
GERP RS		5.1
Varity_R		0.77
Mutation Taster		=85/15	polymorphism

Other links and lift over

dbSNP: rs267606892; hg19: chrM-10564;